Abstract 569: Lymphatic Function Is Impaired Before Atherosclerosis Onset in a Model of Atherosclerosis-prone Mice

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Andreea Milasan ◽  
Marie-Elaine Clavet-Lanthier ◽  
Gaetan Mayer ◽  
Catherine Martel
Keyword(s):  
Lymphatic Vessel ◽  
Lymphatic Vessels ◽  
Ldl Receptor ◽  
Atherosclerotic Lesion ◽  
Lymphatic Transport ◽  
Cellular Transport ◽  
Aortic Sinus ◽  
Lymphatic Function ◽  
Preliminary Results ◽  
Atherosclerosis Progression

Introduction: Macrophages and cholesterol are the two main constituents driving the inflammatory response that characterizes atherosclerosis. In a recent study, the lymphatic system has been identified as a novel prerequisite player in the removal of cholesterol out of the atherosclerotic lesion. It has been shown that without a functional lymphatic network, cholesterol gets trapped in the artery wall. The lymphatic vessels are composed of two main components, namely the absorptive capillaries, responsible for the uptake of the cells, molecules and fluid, and the collecting vessels, characterized by pumping units (lymphangions) that are propelling the lymphatic content toward the blood circulation in a unidirectional manner. The relative roles of the lymphatic capillaries and collectors in the context of atherosclerotic disease are still unclear. Methods and results: Lymphatic function has been evaluated in 3-month old atherosclerosis-prone (LDLR-/-; hApoB100+/+, also called ATX mice), LDLR-/-, atherosclerosis-protected (PCSK9-/- mice, deficient in a convertase that induces the degradation of the LDL receptor) and wild-type (WT) mice. Our preliminary data show that, like LDLR-/- mice, pre-atherosclerotic ATX mice exhibit impaired lymphatic cellular transport. Immunohistochemistry and immunofluorescence imaging portrays a relatively normal number of sprouting and diameter of lymphatic vessel capillaries in the adventitial layer of the aortic sinus and in the skin dermis of ATX mice compared to WT or PCSK9-/- animals. Conclusions: Our preliminary results suggest that lymphatic transport is impaired even before the onset of atherosclerosis, and that i) the LDLR is associated with lymphatic vessel function, and that ii) the collecting lymphatic vessels are most likely responsible for the impairment in lymphatic dysfunction in LDLR-/- and ATX mice. These preliminary results suggest that characterizing the functional pumping capacity of the collecting vessels would be a prerequisite in understanding the interplay between atherosclerosis progression and lymphatic transport. We hope that in the long run we will be able to identify new therapeutic targets to enhance lymphatic transport and ultimately limit atherosclerosis progression.

Abstract 27: ApoA-I Improves Lymphatic Function Through a Platelet-Dependent Mechanism in Atherosclerotic Mice

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Andreea Milasan ◽  
François Dallaire ◽  
Gabriel Jean ◽  
Jean-Claude Tardif ◽  
Yahye Merhi ◽  
...  
Keyword(s):  
Lymphatic Vessel ◽  
Ex Vivo ◽  
Lymphatic Vessels ◽  
Lymphatic Transport ◽  
Lv Function ◽  
Experimental Conditions ◽  
Lymphatic Function ◽  
Beneficial Effects ◽  
Dependent Mechanism

Rationale: Lymphatic vessels (LVs) are now recognized as prerequisite players in the modulation of cholesterol removal from the artery wall in experimental conditions of plaque regression, and a particular attention has been brought on the role of the collecting LVs in early atherosclerosis-related lymphatic dysfunction. Whereas recent findings revealed that apoA-I restores the neovascularization capacity of the lymphatic system during tumor necrosis factor-induced inflammation, the effect of apoA-I on collecting LV function during atherosclerosis has not been tested. Objective: In the present study, we address whether and how apoA-I can enhance collecting LV function in atherosclerosis-associated lymphatic dysfunction. Methods and Results: A 6-week systemic treatment with lipid-free apoA-I enhanced lymphatic transport and abrogated collecting lymphatic vessel permeability in atherosclerotic Ldlr –/– mice when compared to control. As injection of apoA-I has been shown to protect wild-type mice against flow restriction-induced thrombosis, and that platelets are identified as key elements in the maintenance of lymphatic vessel integrity via their interaction with lymphatic endothelial cells (LECs), we have tested whether the effects of apoA-I could be mediated through a platelet-dependent mechanism. Our in vivo results show that apoA-I kinetics in lymph reflected that of blood. Ex vivo experiments performed with washed platelets isolated from mouse blood reveal that apoA-I decreased thrombin-induced but not podoplanin-induced platelet aggregation. Whereas this result suggests that apoA-I limits platelet thrombotic potential in blood but not in lymph, we demonstrate that treatment of human LECs with apoA-I increases the adhesion of bridge-like platelets on human LECs. Conclusions: Our results suggest that apoA-I can mediate beneficial effects on lymphatic function by promoting platelet adhesion to the lymphatic endothelium and consequently restore collecting LV integrity. Altogether, we bring forward a new pleiotropic role for apoA-I in lymphatic function and unveil new potential therapeutic targets for the prevention and treatment of atherosclerosis.

scholarly journals Efficient aortic lymphatic drainage is necessary for atherosclerosis regression induced by ezetimibe

2020 ◽  
Vol 6 (50) ◽  
pp. eabc2697
Author(s):  
Kim Pin Yeo ◽  
Hwee Ying Lim ◽  
Chung Hwee Thiam ◽  
Syaza Hazwany Azhar ◽  
Caris Tan ◽  
...  
Keyword(s):  
Lymphatic Vessels ◽  
Lymphatic Drainage ◽  
Lymphatic Transport ◽  
Atherosclerotic Plaques ◽  
Tissue Fluid ◽  
Atherosclerosis Progression ◽  
Lymphatic Vasculature ◽  
Lesion Regression ◽  
Transport Of Macromolecules

A functional lymphatic vasculature is essential for tissue fluid homeostasis, immunity, and lipid clearance. Although atherosclerosis has been linked to adventitial lymphangiogenesis, the functionality of aortic lymphatic vessels draining the diseased aorta has never been assessed and the role of lymphatic drainage in atherogenesis is not well understood. We develop a method to measure aortic lymphatic transport of macromolecules and show that it is impaired during atherosclerosis progression, whereas it is ameliorated during lesion regression induced by ezetimibe. Disruption of aortic lymph flow by lymphatic ligation promotes adventitial inflammation and development of atherosclerotic plaque in hypercholesterolemic mice and inhibits ezetimibe-induced atherosclerosis regression. Thus, progression of atherosclerotic plaques may result not only from increased entry of atherogenic factors into the arterial wall but also from reduced lymphatic clearance of these factors as a result of aortic lymph stasis. Our findings suggest that promoting lymphatic drainage might be effective for treating atherosclerosis.

Dynamic Role of Macrophage Sub Types for Development of Atherosclerosis and Potential Use of Herbal Immunomodulators as Imminent Therapeutic Strategy

2020 ◽  
Vol 18 ◽  
Author(s):  
Parimalanandhini Duraisamy ◽  
Sangeetha Ravi ◽  
Mahalakshmi Krishnan ◽  
Catherene M. Livya ◽  
Beulaja Manikandan ◽  
...  
Keyword(s):  
Foam Cell ◽  
Cell Formation ◽  
Atherosclerotic Lesion ◽  
Foam Cell Formation ◽  
Atherosclerosis Progression ◽  
Proinflammatory Mediators ◽  
M1 Macrophage ◽  
Tnf Α ◽  
Inflammatory Site

: Atherosclerosis, a major contributor to cardiovascular disease is a global alarm causing mortality worldwide. Being a progressive disease in the arteries, it mainly causes recruitment of monocytes to the inflammatory sites and subside pathological conditions. Monocyte-derived macrophage mainly acts in foam cell formation by engorging the LDL molecules, oxidizes it into Ox-LDL and leads to plaque deposit development. Macrophages in general differentiate, proliferate and undergo apoptosis at the inflammatory site. Frequently two subtypes of macrophages M1 and M2 has to act crucially in balancing the micro-environmental conditions of endothelial cells in arteries. The productions of proinflammatory mediators like IL-1, IL-6, TNF-α by M1 macrophage has atherogenic properties majorly produced during the early progression of atherosclerotic plaques. To counteract cytokine productions and M1-M2 balance, secondary metabolites (phytochemicals) from plants act as a therapeutic agent in alleviating atherosclerosis progression. This review summarizes the fundamental role of the macrophage in atherosclerotic lesion formation along with its plasticity characteristic as well as recent therapeutic strategies using herbal components and anti-inflammatory cytokines as potential immunomodulators.

Heme Oxygenase-1 Inhibits Atherosclerotic Lesion Formation in LDL-Receptor Knockout Mice

2001 ◽  
Vol 88 (5) ◽  
pp. 506-512 ◽  
Author(s):  
Kazunobu Ishikawa ◽  
Daisuke Sugawara ◽  
Xu-ping Wang ◽  
Kazunori Suzuki ◽  
Hiroyuki Itabe ◽  
...  
Keyword(s):  
Heme Oxygenase ◽  
Knockout Mice ◽  
Ldl Receptor ◽  
Atherosclerotic Lesion ◽  
Heme Oxygenase 1 ◽  
Lesion Formation ◽  
Ldl Receptor Knockout Mice ◽  
Atherosclerotic Lesion Formation

scholarly journals Hematopoietic upstream stimulating factor 1 deficiency is associated with increased atherosclerosis susceptibility in LDL receptor knockout mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Menno Hoekstra ◽  
Baoyan Ren ◽  
Pirkka-Pekka Laurila ◽  
Reeni B. Hildebrand ◽  
Jarkko Soronen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Knockout Mice ◽  
Ldl Receptor ◽  
Atherosclerotic Lesion ◽  
Functional Expression ◽  
Upstream Stimulatory Factor ◽  
Wild Type Littermate ◽  
Brown Adipose ◽  
Total Body ◽  
Ldl Receptor Knockout Mice

AbstractTotal body upstream stimulatory factor 1 (USF1) deficiency in mice is associated with brown adipose tissue activation and a marked protection against the development of obesity and atherosclerotic lesions. Functional expression of USF1 has also been detected in monocytes and monocyte-derived macrophages. In the current study we therefore tested whether selective hematopoietic USF1 deficiency can also beneficially impact the development of atherosclerosis. For this purpose, LDL receptor knockout mice were transplanted with bone marrow from USF1 knockout mice or their wild-type littermate controls and subsequently fed a Western-type diet for 20 weeks to stimulate atherosclerotic lesion development. Strikingly, absence of USF1 function in bone marrow-derived cells was associated with exacerbated blood leukocyte (+ 100%; P < 0.01) and peritoneal leukocyte (+ 50%; P < 0.05) lipid loading and an increased atherosclerosis susceptibility (+ 31%; P < 0.05). These effects could be attributed to aggravated hyperlipidemia, i.e. higher plasma free cholesterol (+ 33%; P < 0.001) and cholesteryl esters (+ 39%; P < 0.001), and the development of hepatosteatosis. In conclusion, we have shown that hematopoietic USF1 deficiency is associated with an increased atherosclerosis susceptibility in LDL receptor knockout mice. These findings argue against a contribution of macrophage-specific USF1 deficiency to the previously described beneficial effect of total body USF1 deficiency on atherosclerosis susceptibility in mice.

Abstract 663: Identification of 2 Novel Candidate Genes of Atherosclerosis Susceptibility on Mouse Chromosome 3: Pla2g12a and Elovl6

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Alexandros Nicolaou ◽  
Kristina Sass ◽  
Bernd H Northoff ◽  
Daniel Teupser ◽  
Lesca M Holdt
Keyword(s):  
Western Blot ◽  
Candidate Genes ◽  
Mouse Chromosome ◽  
Blot Analysis ◽  
Western Blot Analysis ◽  
Ldl Receptor ◽  
Atherosclerotic Lesion ◽  
Lesion Size ◽  
Specific Expression ◽  
Qrt Pcr

Quantitative trait locus (QTL) mapping in an F2 intercross (n=452) of atherosclerosis-susceptible C57BL/6 (B6) and atherosclerosis-resistant FVB mice on the LDL-receptor deficient background revealed a novel atherosclerosis susceptibility locus on mouse chromosome (Chr) 3. In previous work the susceptible genetic region on Chr3 was narrowed to 80 - 160 MB and validated by congenic FVB.Chr3 B6/B6 mice. We hypothesized that underlying genetic variation in this region leads to differential expression of causal genes, thereby affecting atherosclerosis susceptibility. We performed transcriptome-wide expression analyses in livers of congenic FVB.Chr3 B6/B6 and FVB mice (n=4/4) using Illumina Ref-8 arrays followed by validation in livers of congenic FVB.Chr3 B6/B6 and FVB mice (n=8/9) as well as in livers of B6 and FVB mice (n=5/5) by quantitative real-time PCR (qRT-PCR). C is -regulation was investigated in F2 livers (n=47) by correlating the expression to the genotype. Tissue-specific expression of genes was examined by qRT-PCR in parental B6 and FVB mice. Western blot analysis and immunohistochemical staining (IHC) were performed. Mechanisms of atherogenesis were investigated by RNAi. Pla2g12a and Elovl6 were identified as candidate genes co-segregating with the atherosclerosis QTL at marker rs13464244. Pla2g12a mRNA expression was inversely correlated (r 2 =0.2, p=0.002) with atherosclerotic lesion size in F2 mice while Elovl6 expression was positively correlated (r 2 =0.18, p=0.002). qRT-PCR revealed a strong expression of Pla2g12a in muscle and fat tissues whereas Elovl6 was highly expressed in liver and fat tissues. Western blot analysis revealed significantly decreased protein expression of Pla2g12a in livers of B6 compared to FVB and an increased expression of Elovl6 in B6 mice. IHC staining of Pla2g12a and Elovl6 in aortic roots indicated high expression in macrophages and predominantly in endothelial cells. siRNA knockdown of Elovl6 was associated with reduced adhesion and increased apoptosis. In conclusion, we identified Elovl6 and Pla2g12a as promising candidate genes of atherosclerosis susceptibility on mouse Chr3. Further work is necessary to better understand the influence of these two genes on atherosclerosis development.

Abstract 366: Biglycan Deficiency Does Not Affect Angiotensin Ii-induced Atherosclerosis but Promotes Aortic Aneurysms Formation

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Tao Tang ◽  
Joel C Thompson ◽  
Patriticia G Wilson ◽  
Meghan H Yoder ◽  
Lisa R Tannock
Keyword(s):  
Aortic Rupture ◽  
Critical Role ◽  
Atherosclerotic Lesion ◽  
Western Diet ◽  
Aortic Aneurysms ◽  
Lesion Area ◽  
Abdominal Aneurysm ◽  
Aortic Sinus ◽  
Face Surface

Background Proteoglycans play a critical role in the development of atherosclerosis due to their ability to bind and retain atherogenic lipoproteins. Of all the vascular proteoglycans, biglycan has been shown to be the one most closely associated with apolipoprotein B. Our previous studies showed that angII increases vascular biglycan content and predisposes to diet-induced atherosclerosis in Ldlr null mice. The purpose of this study was to determine whether biglycan deficiency protected against angII induced atherosclerosis in vivo. Methods and Results Bgn KO or WT mice, crossed to Ldlr null (C57B/6 background), were infused with angII (1000 ng/kg/min) or saline for 28 days followed by 6-week western diet feeding. Bgn KO mice showed no difference in atherosclerotic lesion area at either aortic sinus or en face surface. Unexpectedly, Bgn KO mice exhibited a striking mortality (77% for males and 48% for females) due to aortic rupture upon angII infusion. Thus, a lower dose of angII was then infused to mice to study atherosclerosis. There was no difference in lesion area between Bgn KO or WT mice under angII (500 ng/kg/min) infusion followed by 6-week western diet feeding or under one-year normal chow feeding without angII infusion. However, angII (500 ng/kg/min) still induced greater aortic rupture in Bgn KO mice (30% for males and 13% for females) than in WT mice (0% for both gender). Besides rupture, 7 Bgn KO mice out of 35 also developed aneurysm at mid-thoracic aorta whereas only 1 Bgn WT mouse out of 25 developed abdominal aneurysm after angII (500 ng/kg/min) infusion. Therefore, our study demonstrated that biglycan deficiency did not affect atherosclerotic lesion development, but induced a striking aneurysm phenotype upon angII infusion.

Abstract 1721: Deletion of Both Macrophage ABCG1 and ApoE Independently Promotes Atherosclerotic Lesion Development in LDL Receptor Knockout Mice

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Ruud Out ◽  
Bart Lammers ◽  
Reeni B. Hildebrand ◽  
Carmel M. Quinn ◽  
David Williamson ◽  
...  
Keyword(s):  
Cholesterol Efflux ◽  
Ldl Receptor ◽  
Atherosclerotic Lesion ◽  
Independent Effect ◽  
High Cholesterol Diet ◽  
Moderate Increase ◽  
Lesion Development ◽  
Macrophage Cholesterol Efflux ◽  
Atherosclerotic Lesion Development

Objective ATP-binding cassette transporter G1 (ABCG1) and apolipoprotein E (apoE) play a role in macrophage cholesterol efflux and consequently the development of atherosclerosis. Although a possible interaction between ABCG1 and apoE in cholesterol efflux was postulated, the combined action of these proteins in atherosclerosis is still unclear. Methods and Results LDL receptor knockout (KO) mice were transplanted with bone marrow from ABCG1/apoE double KO (dKO) mice, their respective single knockouts, and wild-type (WT) controls. After feeding a high-fat/high-cholesterol diet for 6 weeks, no differences were found in serum lipid levels. However, the mean atherosclerotic lesion area in dKO transplanted animals (187 ± 18 × 10 3 μ m 2 ) was 1.4-fold (p < 0.01) increased compared to single knockouts (ABCG1 KO: 138 ± 5 × 10 3 μm 2 ; apoE KO: 131 ± 7 × 10 3 μm 2 ) and 1.9-fold (p< 0.001) as compared to WT controls (97 ± 15 × 10 3 μm 2 ). In vitro cholesterol efflux experiments confirmed that combined deletion of ABCG1 and apoE resulted in a larger attenuation of macrophage cholesterol efflux to HDL as compared to single knockouts. Conclusions Deletion of macrophage ABCG1 or apoE does lead to a moderate increase in atherosclerotic lesion development while combined deletion of ABCG1 and apoE induces a more dramatic increase in atherosclerosis. These results indicate an added, independent effect for both macrophage ABCG1 and apoE in atherosclerosis.

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